The serotonin (5-HT) neurotransmitter system is an important target in the quest to understand vulnerability to addiction and relapse, to improve diagnostic and prognostic capabilities with appropriate biomarkers, and importantly to treat this complex disorder. Project 1 of the Translational Center for Serotonin and Stimulant Addiction (TCSSA) will examine the clinical neurobiology of 5-HT^R and 5-HT2cR function in impulsivity and cue reactivity endophenotypes in cocaine-dependent subjects and healthy controls, and examine the specific regulatory effects of the selective serotonin (5-HT) reuptake inhibitor/5-HT2cR agonist escitalopram and the nonselective 5-HT2R antagonist mirtazapine on impulsivity and cue reactivity in human cocaine users. We hypothesize that escitalopram and mirtazapine will significantly reduce behavioral laboratory measures of impulsivity and cue reactivity in cocaine-dependent subjects. Predictors of behavioral effects examined will include: (1) 5-HT2AR and 5-HT2cR function as measured by platelet receptor binding and protein analyses; (2) specific 5-HT^R and 5-HT2CR gene polymorphisms. Secondary measures of cocaine use will also be examined. These experiments will parallel studies to understand the 5-HT^R and 5-HT2CR mechanisms of action in impulsivity and cue reactivity (Project 2) and inform the preclinical projects regarding specific behavioral measures of impulsivity that are responsive to treatment with serotonergic medications. Enhanced understanding of the mechanisms of and the interactions between subject characteristics and medications identified in Project 1 will refine the preclinical behavioral protocols (Project 2). Furthermore, an understanding of the functionality of 5-HT2R systems (Project 1 and 2), expression of specific 5-HT2R genotypes (Core B) and effects of manipulation of serotonergic receptors on cue reactivity and impulsivity measurements (Project 1), will lend significant insight into the role of 5-HT systems in vulnerability to addiction and the potential neuroadaptations in 5-HT signaling that may contribute to withdrawal, abstinence and treatment responses. Lav Abstract. Impulsivity and reactions to cocaine related stimuli are important contributors to initiation and maintenance of cocaine dependence. This project will examine the brain mechanisms responsible for these behaviors. If a greater understanding of the basic brain mechanisms responsible for impulsivity can be determined this will lead to improved treatments for substance abuse and related behaviors.